Carcinoembryonic antigen (CEA)-specific T-cell activation in colon carcinoma induced by anti-CD3 x anti-CEA bispecific diabodies and B7 x anti-CEA bispecific fusion proteins.

Abstract

Two bispecific recombinant molecules, an anti-CD3 x anti-carcinoembryogenic antigen (CEA) diabody and a B7 x anti-CEA fusion protein, were tested for their capacity to specifically activate T cells in the presence of CEA-expressing colon carcinoma cells. T-cell activation by the anti-CD3 x anti-CEA diabody required close contact to CEA-positive cells and resulted in diabody-mediated cytotoxicity against the target cells. Additionally, CD28-mediated costimulation in combination with anti-CD3 x anti-CEA diabodies induced activation of autologous T cells in CEA-positive primary colon carcinoma specimens, as determined by flow cytometry. The high specificity of the bispecific diabody approach could be further enhanced by the use of B7 x anti-CEA fusion proteins because the costimulatory CD28-signaling to the T cells strictly depended on the expression of CEA on the target cells. We demonstrate that displaying engagement sites for the T-cell antigens CD3 and CD28 on the surface of colon carcinoma cells is a suitable way to activate and retarget T cells in a highly tumor-specific manner. For clinical purposes, B7 x anti-tumor-associated antigen (TAA) fusion proteins, which are equally effective but more specific compared with anti-CD28 monoclonal anti-bodies, thus may improve the tumor specificity of anti-CD3 x anti-TAA bispecific antibodies. Furthermore, B7-negative tumors can be converted into B7-positive tumors by B7 x anti-TAA fusion proteins without the need for B7 gene transfer to the malignant cells.

• Authors: P Holliger, O Manzke, M Span, R Hawkins, B Fleischmann, L Qinghua, J Wolf, V Diehl, O Cochet, G Winter, H Bohlen
• Journal: Cancer research (Cancer Res) Vol. 59 Issue 12 Pg. 2909-16 (Jun 15 1999) ISSN: 0008-5472 [Print] United States
• PMID: 10383154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• B7-1 Antigen
• CD28 Antigens
• CD3 Complex
• Carcinoembryonic Antigen
• DNA Primers
• Recombinant Fusion Proteins

Topics

• Amino Acid Sequence
• Antibodies, Bispecific (biosynthesis, immunology)
• B7-1 Antigen (immunology)
• CD28 Antigens (immunology)
• CD3 Complex (immunology)
• Carcinoembryonic Antigen (immunology)
• Colonic Neoplasms (chemically induced, immunology)
• Cytotoxicity, Immunologic
• DNA Primers
• Humans
• Lymphocyte Activation
• Lymphocytes, Tumor-Infiltrating (immunology)
• Molecular Sequence Data
• Recombinant Fusion Proteins (immunology)
• T-Lymphocytes (immunology)